DNA Methylation Changes in Human Papillomavirus-Driven Head and Neck Cancers

Abstract

Disruption of DNA methylation patterns is one of the hallmarks of cancer. Similar to other cancer types, human papillomavirus (HPV)-driven head and neck cancer (HNC) also reveals alterations in its methylation profile. The intrinsic ability of HPV oncoproteins E6 and E7 to interfere with DNA methyltransferase activity contributes to these methylation changes. There are many genes that have been reported to be differentially methylated in HPV-driven HNC. Some of these genes are involved in major cellular pathways, indicating that DNA methylation, at least in certain instances, may contribute to the development and progression of HPV-driven HNC. Furthermore, the HPV genome itself becomes a target of the cellular DNA methylation machinery. Some of these methylation changes appearing in the viral long control region (LCR) may contribute to uncontrolled oncoprotein expression, leading to carcinogenesis. Consistent with these observations, demethylation therapy appears to have significant effects on HPV-driven HNC. This review article comprehensively summarizes DNA methylation changes and their diagnostic and therapeutic indications in HPV-driven HNC.

Molecular Pap Smear: Validation of HPV Genotype and Host Methylation Profiles of ADCY8, CDH8, and ZNF582 as a Predictor of Cervical Cytopathology

“…Published literature on promoter methylation of ADCY8, CDH8 , and ZNF582 has expanded recently and hypermethylation of one or more of these loci have been found in cancers of the breast, oropharynx, esophagus, and anus ( Tang et al, 2019 ; Ekanayake Weeramange et al, 2020 ; Sigin et al, 2020 ; van der Zee et al, 2020 ). These reports not only support the validity of these epigenetic modifications as cancer biomarkers but inform a broader application beyond cervical cancer.…”

“…Methylation status of these markers were predictive of response to neoadjuvant chemotherapy before surgery which may be applicable as a clinical test to guide therapy ( Sigin et al, 2020 ). Second, CDH8 promoter hypermethylation has been documented in four head and neck cancer studies ( Ekanayake Weeramange et al, 2020 ). One such study used PSQ for validation of epigenetic alteration in 70 oropharyngeal squamous cell carcinomas.…”

DNA Methylation in Solid Tumors: Functions and Methods of Detection

“…Finally, distinct precancerous stages of cervical cancer due to HPV16 infection are associated with aberrant methylation profiles of viral E6 gene promoter. E6 protein influences important cellular pathways by inhibiting the action of p53 protein, thus preventing cell cycle arrest and apoptosis and promoting carcinogenesis [ 26 ]. Our group showed that gradual demethylation of HPV E6 promoter correlated with a progression of precancerous lesions [ 27 ].…”

Human Papillomavirus and Cellular Pathways: Hits and Targets

“…This is accomplished and maintained through the action of several enzymes called DNA methyltransferases. In humans, this involves the 5 position of cytosine rings placed at 5 from guanine bases, thus forming CpG islands (reviewed in [187]). Like other epigenetic changes, methylation results in altered gene expression without changing the DNA sequence [188].…”